The simultaneous or sequential use of two or more agents during cancer chemotherapy has often been more effective than single agents against various malignancies. Despite the increasing use of combination chemotherapy relatively little is known about the effects of one anticancer drug on the metabolism, action, or toxicity of a second concurrently administered anticancer drug. Many examples have been described of drug interactions between various types of pharmacologic agents with resultant adverse consequences for the patient. Combination cancer chemotherapy against human solid tumors may involve the use of up to five agents. It seems important to examine the influence of one anticancer drug on the metabolism and antitumor action of a second anticancer drug. We have already shown that treatment of rats with 5- fluorouracil (5-FU) decreased liver microsomal drug-metabolizing enzyme activities and the conversion of cyclophosphamide (CP) to alkylating metabolites. This inhibition may have major pharmacologic consequences since several anticancer drugs used in combination with 5-FU against human solid tumors are metabolized by liver microsomal enzymes. Our objective is to characterize the basis for the alterations in microsomal enzymes activities after 5-FU in our rodent model system. We will also determine the consequences of these enzymatic alterations on the metabolism and anticancer action of CP and other agents, used in combination with 5-FU, and which are metabolized by microsomal enzymes. Furthermore a second anticancer drug, e.g. CP, will be compared with 5- FU as to its effects on microsomal enzyme activities and the metabolism of other anticancer drugs. The presence of tumor itself alters microsomal enzyme activities. We will determine the effects of 5-FU on drug-metabolizing enzymes and the metabolism of other anticancer drugs in solid tumor-bearing rats. A better understanding of drug interactions arising as a consequence of the effects of anticancer drug treatment on microsomal enzyme activities will serve as a useful guide to increase the effectiveness of drug combinations involing 5-FU which are used against human solid tumors.